Imidazolyl thiopehene sulfonyl carbamates for use in the treatment of diseases associated with angiotensin ii

Abstract

There is provided herein a compound of formula (I), wherein R1, R2, R3, R4, R5 and Z are as defined herein, for use in the treatment of a disease or condition in which activation of AT2 receptors is desired or required but in which inhibition of CYPs is not desired. Such compounds are particularly useful in the treatment of autoimmune and/or fibrotic diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis.

1 . A method of treating a disease or condition in which activation of AT2 receptors is desired or required but in which inhibition of CYPs is not desired, which method comprises administering to a patient in need of a therapeutically effective amount of a compound of formula I, 
       
         
           
           
               
               
           
         
         wherein: 
         Z represents —O— or a direct bond; 
         R 1  represents C 1-3  alkyl, optionally substituted by one or more halogen atoms; 
         R 2  and R 3  each independently represent H or C 1-3  alkyl, optionally substituted by one or more halogen atoms; 
         R 4  represents C 1-6  alkyl or C 1-6  alkoxy, each of which is optionally substituted with one or more halogen atoms, or 
         R 4  represents aryl, C 1-6  alkylaryl, heteroaryl or C 1-6  alkylheteroaryl, each of which is optionally substituted by one or more substituents selected from halogen, —CH 2 F, —OCF 3 , 
         C 1-6  alkyl, and C 1-6  alkoxy; 
         R 5  represents C 1-6  alkyl, C 1-6  alkoxy or C 1-6  alkoxy-C 1-6 alkyl, each of which is optionally substituted by one or more halogen atoms, 
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein Z represents —O—. 
     
     
         3 . The method of  claim 1  wherein R 1  represents methyl or ethyl. 
     
     
         4 . The method of  claim 1  wherein R 2  and R 3  independently represent H, methyl or ethyl. 
     
     
         5 . The method of  claim 1  wherein R 4  represents a C 1-4  alkyl group, optionally substituted or terminated by up to three fluorine atoms; phenyl; C 1-3  alkylaryl; or C 1-3  alkylheteroaryl. 
     
     
         6 . The method of  claim 1  wherein R 5  represents a C 1-4  alkyl group, optionally substituted or more preferably terminated by up to three fluorine atoms. 
     
     
         7 . The method of  claim 1 , wherein the compound of Formula 1 is:
 butyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate;   butyl (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate; or   ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.   
     
     
         8 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, provided that when: Z represents —O—; R 1  represents methyl; R 2  and R 3  both represent H; and R 4  represents n-butyl, then R 5  does not represent isobutyl. 
     
     
         9 . A compound as claimed in  claim 8 , which is:
 butyl (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate; or   ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.   
     
     
         10 . (canceled) 
     
     
         11 . A pharmaceutical formulation comprising a compound as defined in  claim 8  in admixture with a pharmaceutically-acceptable, adjuvant, diluent or carrier. 
     
     
         12 . A method of treating a disease or condition in which activation of AT2 receptors is desired or required but in which inhibition of CYPs is not desired, which method comprises administering to a patient in need of a therapeutically effective amount of a compound as defined in  claim 8 . 
     
     
         13 . A pharmaceutical formulation comprising a compound as defined in  claim 1 ; a therapeutic agent that is known to be metabolized by a CYP enzyme; and a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     
     
         14 . A kit of parts comprising:
 (A) a pharmaceutical formulation including a compound as defined in  claim 1  in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and   (B) a pharmaceutical formulation including a therapeutic agent that is known to be metabolized by a CYP enzyme, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,   which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.   
     
     
         15 . The formulation as claimed in  claim 13 , wherein the therapeutic agent is selected from the group pirfinidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, simvastatin, and pharmaceutically-acceptable salts of any of those agents. 
     
     
         16 . A method of treating a disease or condition in which activation of AT2 receptors is desired or required but in which inhibition of CYPs is not desired, which method comprises administering to a patient in need of a formulation as claimed in  claim 13 . 
     
     
         17 . The method as claimed in  claim 16 , wherein the disease or condition to be treated is selected from the group: an interstitial lung disease, an autoimmune disease, a chronic kidney disease, pulmonary hypertension, an obstructive airway disease, a viral respiratory tract infection and pneumonia as a consequence thereof and infarction. 
     
     
         18 . The method as claimed in  claim 17 , wherein the disease or condition is selected from the group: rheumatoid arthritis, diabetic nephropathy, pulmonary arterial hypertension, chronic obstructive airway disease, virally-induced pneumonia and myocardial infarction. 
     
     
         19 . The method as claimed in  claim 17 , wherein the disease is an interstitial lung disease. 
     
     
         20 . The method as claimed in  claim 19 , wherein the interstitial lung disease is idiopathic pulmonary fibrosis. 
     
     
         21 . The method as claimed in  claim 19 , wherein the interstitial lung disease is sarcoidosis. 
     
     
         22 . The method as claimed in  claim 19 , wherein the therapeutic agent that is known to be metabolized by a CYP enzyme is pirfenidone, or a pharmaceutically-acceptable salt thereof. 
     
     
         23 . A process for the preparation of a compound of formula I as defined in  claim 8 , which process comprises:
 (i) reaction of a compound of formula II,   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 5  are as defined in  claim 8 , with a compound of formula III, 
       
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are as defined in  claim 8 ; and X represents a suitable leaving group. 
       
     
     
         24 . The kit of parts as claimed in  claim 14 , wherein the therapeutic agent is selected from the group pirfinidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, simvastatin, and pharmaceutically-acceptable salts of any of those agents. 
     
     
         25 . A method of treating a disease or condition in which activation of AT2 receptors is desired or required, but in which inhibition of CYPs is not desired, which method comprises administering to a patient in need of a kit of parts as claimed in  claim 14 . 
     
     
         26 . The method as claimed in  claim 25 , wherein the disease or condition to be treated is selected from the group: an interstitial lung disease, an autoimmune disease, a chronic kidney disease, pulmonary hypertension, an obstructive airway disease, a viral respiratory tract infection and pneumonia as a consequence thereof and infarction. 
     
     
         27 . The method as claimed in  claim 26 , wherein the disease or condition is selected from the group: rheumatoid arthritis, diabetic nephropathy, pulmonary arterial hypertension, chronic obstructive airway disease, virally-induced pneumonia and myocardial infarction. 
     
     
         28 . The method as claimed in  claim 26 , wherein the disease is an interstitial lung disease. 
     
     
         29 . The method as claimed in  claim 28 , wherein the interstitial lung disease is idiopathic pulmonary fibrosis. 
     
     
         30 . The method as claimed in  claim 28 , wherein the interstitial lung disease is sarcoidosis. 
     
     
         31 . The method as claimed in  claim 14 , wherein the therapeutic agent that is known to be metabolized by a CYP enzyme is pirfenidone, or a pharmaceutically-acceptable salt thereof. 
     
     
         32 . A pharmaceutical formulation comprising a compound as defined in  claim 9  in admixture with a pharmaceutically-acceptable, adjuvant, diluent or carrier. 
     
     
         33 . A method of treating-a disease or condition in which activation of AT2 receptors is desired or required but in which inhibition of CYPs is not desired, which method comprises administering to a patient in need of a therapeutically effective amount of a compound as defined in  claim 9 . 
     
     
         34 . A pharmaceutical formulation comprising a compound as defined in- claim 8 ; a therapeutic agent that is known to be metabolized by a CYP enzyme; and a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     
     
         35 . A kit of parts comprising:
 (A) a pharmaceutical formulation including a compound as defined in  claim 8 , in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and   (B) a pharmaceutical formulation including a therapeutic agent that is known to be metabolized by a CYP enzyme, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,   which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.